Three separate recombinant or peptide vaccines have been shown to protect macaques from an intravenous challenge with simian immunodeficiency virus (SIV) or type D retrovirus (SRV-2). Macaques immunized with a vaccinia recombinant expressing the envelope proteins of our molecular clone of SRV-2/WASHINGTON (gp7O and gp22) were protected against a homologous challenge with 10 to the sixth power infectious particles of SRV-2. Vaccinated animals are not infected one year after challenge as determined by failure to isolate virus or lack of seroconversion to additional viral proteins. These animals are now being challenged with a heterologous strain (SRV-1). One of the potential difficulties in developing an HIV vaccine involves the large variation in the V-3 loop of the envelope protein gpl2O among various isolates. Four peptides representing highly conserved and seroprevalent regions of gpl2O and gp4l were mixed and used as immunogens in three rhesus macaques. The 2 animals with the highest neutralizing titers resisted a challenge of 100 infectious particles of SIV. One year after challenge, whole blood and lymph node cells were passaged to other macaques; there is no evidence of infection in the recipient animals by eight weeks after transfer. In a third experiment, macaques have also been immunized with two doses of a vaccinia virus recombined with and expressing the envelope proteins (gpl2O and gp32) of our pathogenic molecular clone of SIV/Mne. After being boosted with gpl6O protein expressed in baculovirus, these animals were challenged intravenously with 10 animal-infectious doses of SIV/Mne. Eight months later, these animals show no evidence of virus infection. These experiments are the first description of successful recombinant vaccines that protect against SIV infection and suggest that similar approaches may be directly applicable to HIV vaccine development. These studies have been facilitated by the use of well-defined stocks of virus that have been titered in various cell lines in vitro as well as in macaques.